Beta-receptor antagonists have variable but demonstrable antiarrhythmic efficacy, and substantial evidence has indicated that some of these agents can reduce the incidence of sudden cardiac death. The mechanisms of these actions are poorly understood, and there is no data to indicate that prevention of sudden death requires either Beta-blockade or antiarrhythmic efficacy. Since some patients may not require the Beta-blocking action and because many with heart failure or asthma cannot tolerate this class of drugs, agents able to prevent sudden death without blockade of Beta-receptors would be desirable for a subset of the population at risk. We have previously found that 40% of patients with ventricular arrhythmias require plasma propranolol concentrations well above those producing Beta-blockage for antiarrhythmic efficacy. In animal studies we compared the electrophysiologic effects of d-propranolol (a weakly active Beta-blocker) and dl-propranolol at equivalent levels of Beta-blockade. We found additional electrophysiologic actions of d-propranolol at the high concentrations achieved. These effects were also present at high concentrations of dl-propranolol and were not reversed by isoproterenol infusion. We have also compared the electrophyslologic actions of low (60-140 ng/ml) and high (250-700 ng/ml) concentrations of dl-propranolol in man. We have again identified actions which could be antiarrhythmic at concentrations higher than those required for Beta-adrenergic blockade. Because our data indicate that propranolol has antiarrhythmic actions unrelated to its Beta-blocking action, we propose to study the antiarrhythmic efficacy and electrophysiologic actions of d-propranolol in man. To determine if these actions are unique to the d-isomer of propranolol, we propose to compare in patients with ventricular arrhythmias the efficacy of dl-propranolol and l-timolol (a Beta-antagonist lacking propranolol's membrane depressant activity). We also propose to similarly compare these drugs to sotalol, a Beta-antagonist which has additional ability to increase ventricular refractoriness. All three drugs will be given above equivalent high degrees of Beta-blockade to see if any have additional efficacy. This comparison should identify and antiarrhythmic action of these drugs which is dissociated with Beta-blockade. These studies could allow the design of agents with antiarrhythmic efficacy devoid of the potentially undesirable Beta-adrenergic blocking actions. Likewise, the studies should provide a better understanding of the possible mechanisms of action of agents, such as timolol, which have already proven their ability to prevent sudden death.